© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Role of Serum Amyloid A During Metabolism of Acute-Phase HDL by Macrophages
From Karl-Franzens University Graz (A.A., G.M., W.S., E.M.), Institute of Medical Biochemistry, Graz, Austria, and Unité INSERM 325 (S.L.), Institut Pasteur, Lille, France.
Correspondence to Dr Ernst Malle, Karl-Franzens University Graz, Institute of Medical Biochemistry, Harrachgasse 21, A-8010 Graz, Austria. E-mail ernst.malle{at}kfunigraz.ac.at
Abstract—The serum amyloid A
(SAA) family of proteins is encoded by multiple genes that display
allelic variation and a high degree of homology in mammals. Triggered
by inflammation after stimulation of hepatocytes by
lymphokine-mediated processes, the concentrations of SAA may increase
during the acute-phase reaction to levels 1000-fold greater than those
found in the noninflammatory state. In addition to its role as an
acute-phase reactant, SAA (104 amino acids, 12 kDa) is considered to be
the precursor protein of secondary reactive amyloidosis, in which the
N-terminal portion is incorporated into the bulk of
amyloid fibrils. However, the association with lipoproteins of the
high-density range and subsequent modulation of the
metabolic properties of its
physiological carrier appear to be the principal
role of SAA. Because SAA may displace apolipoprotein A-I, the major
protein component of native high density lipoprotein (HDL), during the
acute-phase reaction, the present study was aimed at (1)
investigating binding properties of native and acute-phase
(SAA-enriched) HDL by J774 macrophages, (2) elucidating whether
the presence of SAA on HDL particles affects selective uptake of
HDL-associated cholesteryl esters, and (3) comparing cellular
cholesterol efflux mediated by native and acute-phase HDL.
Both the total and the specific binding at 4°C of rabbit acute-phase
HDL were 
2-fold higher than for native HDL. Nonlinear regression
analysis revealed Kd values of
7.0x10-7 mol/L (native HDL) and 3.1x10-7
mol/L (acute-phase HDL), respectively. The corresponding
Bmax values were 203 ng of total lipoprotein per milligram
of cell protein (native HDL) and 250 ng of total lipoprotein per
milligram of cell protein (acute-phase HDL). At 37°C, holoparticle
turnover was slightly enhanced for acute-phase HDL, a fact reflected by
2-fold higher degradation rates. In contrast, the presence of SAA on
HDL specifically increased (1.7-fold) the selective uptake of HDL
cholesteryl esters from acute-phase HDL by J774 macrophages, a
widely used in vitro model to study foam cell formation and
cholesterol efflux properties. Although ligand blotting
experiments with solubilized J774 membrane proteins failed to identify
the scavenger receptor-BI as a binding protein for both native and
acute-phase HDL, 2 binding proteins with molecular masses of 100 and 72
kDa, the latter comigrating with CD55 (also termed decay-accelerating
factor), were identified. During cholesterol efflux
studies, it became apparent that the ability of acute-phase HDL with
regard to cellular cholesterol removal was considerably
lower than that for native HDL. This was reflected by a 1.7-fold
increase in 
/2 values (22 versus 36 hours; native versus acute-phase
HDL). Our observations of increased HDL cholesteryl ester uptake and
reduced cellular cholesterol efflux (acute-phase versus
native HDL) suggest that displacement of apolipoprotein A-I by SAA
results in considerable altered metabolic properties of its
main physiological carrier. These changes in the
apolipoprotein moieties appear (at least in the in vitro system tested)
to transform an originally antiatherogenic into a proatherogenic
lipoprotein particle.
Key Words: inflammation • cholesterol metabolism • HDL
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